A Brief Review of Alanine Aminotransferase Activity

L. Dawn Figlio, DVM; Heather L. Tarpley, DVM; Kenneth S. Latimer, DVM, PhD; Perry J. Bain, DVM, PhD

Class of 2004 (Figlio) and Department of Pathology (Tarpley, Latimer, Bain), College of Veterinary Medicine, University of Georgia, Athens, GA 30602-7388

Introduction

The enzyme alanine aminotransferase (ALT) was previously known as serum glutamic pyruvic transaminase (SGPT).² This enzyme also is correctly referred to as alanine transaminase.^4,8 ALT is a cytoplasmic enzyme that catalyzes the transamination of alpha-ketoglutarate and L-alanine, forming glutamate and pyruvate (Fig. 1). This chemical reaction is reversible.^2,8

Figure 1. Enzymatic function of alanine aminotransferase in the transamination of alpha-ketoglutarate and L-alanine to glutamate and pyruvate

The highest activities of ALT are found in hepatocytes and striated (skeletal and cardiac) muscle cells.^2,9 Therefore, increased serum ALT activity can accompany hepatocellular injury or necrosis of striated muscle.^2,9 With cell injury or death, ALT (a "leakage" enzyme) escapes from the cytosol. Determination of ALT activity is a relatively sensitive indicator of hepatic damage in certain animal species and can help determine whether further diagnostic tests (i.e., determination of creatine kinase activity, bile acid concentration, or a liver biopsy) are necessary. ² Mechanisms of increased activity of ALT in serum include enzyme release from damaged cells or induction of enzyme activity (increased enzyme synthesis) from drug administration. Release of ALT from the cytosol can occur secondary to cellular necrosis or as a result of cellular injury with membrane damage and bleb formation.⁸

Clinical Significance of Alanine Aminotransferase

In dogs, cats, rats, rabbits, and primates, ALT activity is highest in hepatocytes. Therefore, elevations in serum ALT activity are considered to be relatively specific for liver disease. However, measurement of serum ALT activity does not test hepatic integrity alone because increased serum ALT activity also may occur with striated muscle necrosis or injury.^8,9 Ruminants, pigs, horses, and birds have a much lower level of hepatocellular ALT activity. In these species, increased serum ALT activity usually is a reflection of skeletal muscle necrosis.²

The half-life of ALT is approximately 60 hours (2-3 days) in dogs and less than 24 hours in cats.^2,8 After the initial liver damage, serum ALT activity increases within the first 12 hours, peaks at 1-2 days, and returns to the reference interval within 2-3 weeks.² To differentiate muscle damage from hepatocyte damage, serum creatine kinase (CK, CPK)activity should be measured. Increased serum CK activity indicates a muscular insult.⁹ Canine X-linked muscular dystrophy and myopathies with ongoing necrosis have been associated with persistently elevated ALT activity.⁹ Increased ALT activity without a concurrent increase in CK activity suggests hepatocellular damage. Increased ALT activity can be caused by reversible or irreversible damage to hepatocytes including necrosis, ischemia, enzyme induction (i.e., anticonvulsants, glucocorticoids, and thiacetarsemide), drug-induced hepatotoxicity (i.e., tetracycline in cats, carprofen in dogs), cholestasis, and trauma.^1,2,3-6 These forms of hepatic damage can be acute or chronic. Acute hepatocellular injury tends to result in greater elevations of ALT activity. In chronic hepatic disease, ALT activity may be within the reference interval or mildly elevated.²

Sample Handling

Because hemolysis can cause a mild increase in ALT activity, careful sample collection and handling is important.⁷ Lipemia also can cause an artifactual increase in ALT activity in endpoint or nonkinetic assays.⁷ Improper sample handling leading to enzyme degradation may result in artifactually decreased ALT values.⁸ Serum samples can be stored up to 24 hours in a refrigerator or at room temperature without appreciable loss of ALT activity.⁷ The ALT activity of serum samples is fairly stable, as long as the serum is not frozen and thawed repeatedly, stored at 20^oC for longer than two days, or stored at 0^o to 4^oC for longer than one week.^8,9

Conclusions

Although ALT activity is considered to be liver specific in the dog and cat, increased ALT activity does not specify the cause of the hepatic damage, distinguish focal versus diffuse hepatic disease, or determine the reversibility of the damage.⁸ With increases in ALT activity (especially mild increases), it is important to consider creatine kinase activity to determine whether the increased ALT activity is due to hepatic or muscular damage. In addition, consideration should be given to concurrent diseases and drug administration, since some drugs cause hepatotoxicity or induce enzyme activity. The degree of increase in ALT activity correlates with the number of hepatocytes damaged, which may be useful in helping to evaluate the extent of hepatic damage.² ALT activity may also increase following release from hepatocytes during liver repair.² In contrast, increased ALT activity may be mild or absent in chronic diseases with hepatic fibrosis.²

Differentiation of acute injury from an ongoing disease process may require collection and evaluation of several serum samples a few days apart. Knowledge of expected peak activity of ALT, enzymatic half-life, and anticipated return of ALT activity to the reference interval will facilitate clinical interpretation of laboratory data. For example, a more favorable prognosis may be indicated in acute hepatic injury when ALT activity decreases significantly after the 1-2 day peak, as compared to patients whose ALT activity fails to decrease. In summary, although determination of ALT activity has its limitations, it can be a useful aid in the diagnosis of hepatocellular injury.

References

1. Aitken MM, Hall E, Scott L, Davot JL, Allen WM: Liver-related biochemical changes in the serum of dogs being treated with phenobarbitone. Vet Rec 153:13-16, 2003.

2. Bain PJ: Liver. In: Latimer KS, Mahaffey EA, Prasse KW: Duncan and Prasse's Veterinary Laboratory Medicine: Clinical Pathology, 4th ed. Ames, Iowa State Press, 2003, pp. 193-214.

3. Hadley SP, Hoffmann WE, Kuhlenschmidt MS, Sanecki RK, Dorner JL: Effect of glucocorticoids on alkaline phosphatase, alanine aminotransferase, and gamma-glutamyltransferase in cultured dog hepatocytes. Enzyme 43:89-98, 1990.

4. Kaufman AC, Greene CE: Increased alanine transaminase activity associated with tetracycline administration in a cat. J Am Vet Med Assoc 202:628-630, 1993.

5. MacPhail CM, Lappin MR, Meyer DJ, Smith SG, Webster CR, Armstrong PJ: Hepatocellular toxicosis associated with administration of carprofen in 21 dogs. J Am Vet Med Assoc. 212:1895-1901, 1998.

6. Muller PB, Taboada J, Hosgood G, Partington BP, VanSteenhouse JL, Taylor HW, Wolfsheimer KJ: Effects of long-term phenobarbital treatment on the liver in dogs. J Vet Intern Med 14:165-171, 2000.

7. Pratt PW: Laboratory Procedures For Veterinary Technicians, 3rd ed. Philadelphia, Mosby, 1996, pp. 98-99.

8. Stockham SL, Scott MA: Fundamentals of Veterinary Clinical Pathology. Ames, Iowa State University Press, 2002, pp. 434-459

9. Valentine BA, Blue JT, Shelley SM, Cooper BJ: Increased serum alanine aminotransferase activity associated with muscle necrosis in the dog. J Vet Intern Med 4:140-143, 1990.

Acknowledgement

Top illustration: Model of a branched chain amino acid transferase is from Professor Ken Hirotsu's web site, Laboratory for Biological Structural Chemistry: Structure-Function Relationship of Enzymes and Protein Crystallography

Figure 1: is from the CHU-PS website at http://www.chups.jussieu.fr/polys/biochimie/EEbioch/POLY.Chp.7.10.html

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